Cannabinoids are lipid-based compounds that can be divided into endogenous cannabinoids (endocannabinoids), which are generated naturally inside the body, from exogenous cannabinoids, which are introduced into the body as cannabis or a related synthetic compound. The physiological effects of cannabinoids are mediated by at least two high-affinity cannabinoid receptors, CB1 and CB2, located in the cell membrane. Belonging to a class of G-protein coupled receptor (GPCR) family, CB1 and CB2 share about 44% amino acid sequence identity. Both CB1 and CB2 receptors couple to the inhibitory G-protein alpha-subunit Gi and G0. Receptor activation thus leads to inhibition of adenylate cyclase, thereby the production of the second messenger molecule cyclic AMP, as well as to activation of mitogen activated protein kinase (MAPK). In addition, under certain conditions and with certain agonists, the CB1 and CB2 receptors couple to Gs and Gq11. Furthermore, CB1 and CB2 receptor activation also although appears to have distinct downstream effects on other intracellular signal transduction pathways, such as, e.g., potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun, depending on the cell type. D. G. Demuth and A. Molleman, Cannabinoid Signaling, Life Sci. 78(6): 549-563 (2006). CB1 receptors can also modulate ion channels, inhibiting N-, and P/R-type calcium channels, stimulating inwardly rectifying K channels and enhancing the activation of the A-type K channel.
The therapeutic use of cannabinoids dated back at least 4,000 years to the ancient dynasties of China and includes applications for various illnesses ranging from lack of appetite, emesis, cramps, menstrual pain, spasticity to rheumatism. The long history of medicinal use of cannabinoids has led to the development of several modern pharmaceutical drugs. For example, MARINOL (generic name dronabinol) and CESAMET (generic name nabilone), two synthetic cannabinoids based on THC, are prescribed anti-emetic and for enhancement of appetite, mainly in AIDS patients. In addition to their clinical use as an antiemetic, potential therapeutic uses of nonselective cannabinoid receptor agonists include the management of multiple sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilatation that accompanies advanced cirrhosis, and cancer. See e.g., Y. Cheng and S. A. Hitchcock, Targeting Cannabinoid Agonists for Inflammatory and Neuropathic Pain, Expert Opin. Investig. Drugs 16(7): 951-965 (2007); B. G. Ramíirez, et al., Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation, J. Neurosci. 25(8): 1904-1913 (2005).
However, despite the clinical benefits, the therapeutic usage of current cannabinoid agonists is limited by their clinically undesirable psychotropic side-effects, such as, e.g., hallucination, addiction, and dependence. With the discovery that these psychotropic side-effects were mediated by the CB1 receptor, great interest has been focused on identifying CB2 selective agonists in an effort to develop pharmaceutical drugs that lack the psychotropic side-effects associated with nonselective CB1/CB2 cannabinoid agonists. See e.g., Meyyappan Muthuppalaniappan, et al., Novel Cannabinoid Receptor Ligands, Pharmaceutical Compositions Containing Them, and Processes for Their Preparation, U.S. Patent Publication 2008/0200501; Chunjian Liu, et al., Indole Indane Amide Compounds Useful as CB2 Agonists and Method, U.S. Patent Publication 2009/0041722; Timothy C. Gahman, et al., Heterocyclodiazeoine Cannabinoid Receptor Modulators for Treatment of Disease, U.S. Patent Publication 2009/0062253; Tomoki Kato, et al., Sulfonyl Benzimidazole Derivatives, U.S. Patent Publication 2009/0137584; Liotta Fina, et al., Hexahydro-Cycloheptapyrazole Cannabinoid Modulators, US Patent Publication 2009/0197886; Mingde Xia, et al., Method for Treating CB2 Receptor Mediated Pain, U.S. Patent Publication 2009/0215850; and Doria Riether, et al., Compounds which Modulate the CB2 Receptor, U.S. Patent Publication 2009/0275611; each of which is hereby incorporated by reference in its entirety.
The present specification discloses novel CB2 agonist useful for treating a variety of diseases mediated by CB2 receptor activity, including inflammatory pain, reflex sympathetic dystrophy/causalgia, peripheral neuropathy, entrapment neuropathy, complex regional pain syndrome, nociceptive pain, neuropathic pain, fibromyalgia, chronic low back pain, visceral pain, acute cerebral ischemia, pain, chronic pain, acute pain, post herpetic neuralgia (PHN), neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, ocular pain, headaches of various etiologies, including migraine, acute herpes zoster (shingles), pain-related disorders such as tactile allodynia and hyperalgesia, rheumatoid arthritic pain, osteoarthritic pain, back pain, cancer pain, dental pain, muscular pain, mastalgia, pain resulting from dermal injuries, fibromyalgia, neuritis, sciatica, inflammation, neurodegenerative disease, cough, broncho constriction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, cerebrovascular ischemia, emesis such as cancer chemotherapy-induced emesis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, dermatitis, seasonal allergic rhinitis, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorders, irritable bowel syndrome, cutaneous T cell lymphoma, multiple sclerosis, osteoarthritis, psoriasis, systemic lupus erythematosus, diabetes, glaucoma, osteoporosis, glomerulonephritis, renal ischemia, nephritis, hepatitis, cerebral stroke, vasculitis, myocardial infarction, cerebral ischemia, reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, and bronchitis.
Aspects of the present specification relate to a compound of formula I:
                wherein R, R1, R2, and R3, are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl; and        Q is aryl, a substituted aryl, or the ring-structure of formula II:        
                wherein Y is N, O, S or C(R6R7); and        R6, R7, R8, R9, R10, R11, R12, R13, R14, and R15 are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl.        
In other aspects, the present specification relate to a compound of formula I:
                wherein R is H, halogen, hydroxyl, oxo, keto, C1-C6 alkyl, or OC1-C6 alkyl;        R1 is H, halogen, hydroxyl, oxo, keto, C1-C6 alkyl, or OC1-C6 alkyl;        R2 is H, halogen, hydroxyl, oxo, keto, C1-C6 alkyl, OC1-C6 alkyl, or C2-C6 alkyl substituted by N(R4R5), or C2-C6 alkyl substituted by OH;        R3 is H, halogen, hydroxyl, oxo, keto, C1-C6 alkyl, or OC1-C6 alkyl;        R4 and R5 are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl; and        Q is phenyl, a substituted phenyl, or the ring-structure of formula II:        
                wherein Y is O or C(R6R7); and        R6, R7 R8, R9, R10, R11, R12, R13, R14, and R15 are independently H, hydroxyl, halogen, oxo, keto, C1-C6 alkyl, or OC1-C6 alkyl.        
In yet other aspects, the present specification relate to a compound of formula I:
                wherein R is H, halogen, hydroxyl, oxo, keto, C1-C3 alkyl, or OC1-C3 alkyl;        R1 is H, halogen, C1-C3 alkyl, or OC1-C3 alkyl;        R2 is C1-C6 alkyl, C2-C6 alkyl substituted by N(R4R5), or C2-C6 alkyl substituted by OH;        R3 is H, or C1-C6 alkyl;        R4 and R5 are independently C1-C4 alkyl, morpholine, or piperidine; and        Q is the ring-structure of formula II:        
                wherein Y is O or C(R6R7);        R6 and R7 are independently H or halogen; and        R8, R9, R10, R11, R12, R13, R14, and R15 are independently H or C1-C2 alkyl, provided at least two are not hydrogen.        
In a further aspect, the compound is of formula I wherein R8, R9, R14, and R15 are methyl; R10, R11, R12, and R13 are hydrogen; and Y is CH2. In yet further aspects, the compound is 5-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4,5-Dichloro-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Chloro-5-methylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Chloro-5-dimethylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Chloro-5-propylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 5-Methylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 5-Dimethylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 5-Propylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 5-Propyloxy-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Chloro-5-(2-morpholin-4-ylethylamino)-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Chloro-5-(2-dimethylaminoethylamino)-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Bromo-5-propylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Bromo-5-(2-dimethylaminoethylamino)-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Bromo-5-(2-morpholin-4-ylethylamino)-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, 4-Chloro-5-(2-dimethylamino ethylmethylamino)-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one, or 4-Chloro-5-(2-diethylaminoethylamino)-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one.
In other aspects of the present specification relate to a compound of formula III:
                wherein X is N, O, S or C(R4R5)        W is N, O, S, or CH;        R1 and R2 are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl;        R4 and R5 are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl; and        Q is phenyl, a substituted phenyl, or the ring-structure of formula II:        
                wherein Y is N, O, S or C(R6R7); and        R6, R7, R8, R9, R10, R11, R12, R13, R14, and R15 are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl.        
In yet other aspects of the present specification relate to a compound of formula III:
                wherein X is N or CH;        W is N or CH;        R1 is H, halogen, hydroxyl, oxo, keto, C1-C6 alkyl, or OC1-C6 alkyl;        R2 is H, halogen, hydroxyl, oxo, keto, C1-C6 alkyl, OC1-C6 alkyl, C2-C6 alkyl substituted by N(R4R5), or CC2-C6 alkyl substituted by OH;        R4 and R5 are independently H, hydroxyl, halogen, oxo, keto, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted alkenyl, unsubstituted or optionally substituted alkynyl, unsubstituted or optionally substituted oxyalkyl, unsubstituted or optionally substituted thioalkyl, a six-member cycloalkyl, a six-member heterocycloalkyl, a six-member aryl, or a six-member heteroaryl; and        Q is phenyl, a substituted phenyl, or the ring-structure of formula II:        
                wherein Y is O or C(R6R7); and        R6, R7 R8, R9, R10, R11, R12, R13, R14, and R15 are independently H, hydroxyl, halogen, oxo, keto, C1-C6 alkyl, or OC1-C6 alkyl.        
In yet other aspects of the present specification relate to a compound of formula III:
                wherein R is H, halogen, C1-C3 alkyl, or OC1-C3 alkyl;        R1 is H, halogen, C1-C3 alkyl, or OC1-C3 alkyl;        R2 is C1-C6 alkyl, C2-C6 alkyl substituted by N(R4R5), or C2-C6 alkyl substituted by OH;        R4 and R5 are independently C1-C4 alkyl, morpholine, or piperidine;        X is N or CH;        W is N or CH; and        Q is the ring-structure of formula II:        
                wherein Y is O or C(R6R7);        R6 and R7 are independently H or halogen; and        R8, R9, R10, R11, R12, R13, R14, and R15 are independently H or C1-C2 alkyl, provided at least two are not hydrogen.        
In a further aspect of this composition, the compound is of formula III wherein R8, R9, R14, and R15 are methyl; R10, R11, R12, and R13 are hydrogen; and Y is CH2. In yet further aspects of this composition, the compound is 1-Propyl-5-(3,3,5,5-tetramethyl cyclohexyl)pyrazolo[3,4-d]pyridazin-4-one, 2-Propyl-5-(3,3,5,5-tetramethyl cyclohexyl)pyrazolo[3,4-d]pyridazin-4-one, 1-(2-Morpholin-4-ylethyl)-5-(3,3,5,5-tetramethylcyclohexyl)pyrazolo[3,4-d]pyridazin-4-one, 2-(2-Morpholin-4-ylethyl)-5-(3,3,5,5-tetramethylcyclohexyl)pyrazolo[3,4-d]pyridazin-4-one, 1-(2-Dimethylaminoethyl)-5-(3,3,5,5-tetramethylcyclohexyl)pyrazolo[3,4-d]pyridazin-4-one, or 2-(2-Dimethylaminoethyl)-5-(3,3,5,5-tetramethylcyclohexyl)pyrazolo[3,4-d]pyridazin-4-one.
Other aspects of the present specification relate to compositions comprising a compound of formula I or a compound of formula III. In a further aspect of this composition, the composition is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, in admixture with a non-toxic, pharmaceutically acceptable vehicle. In a yet further aspect of this composition, the composition is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula III, in admixture with a non-toxic, pharmaceutically acceptable vehicle.
Yet other aspects of the present specification relate to methods of treating an individual suffering from a disease, the method comprising the step of administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, wherein such administration reduces or eliminates a symptom associated with the disease.
Yet other aspects of the present specification relate to methods of treating an individual suffering from a disease, the method comprising the step of administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula III, wherein such administration reduces or eliminates a symptom associated with the disease.